Pipecolamide derivatives, particularly in optically active forms thereof, are useful as an intermediate in the manufacturing of topical anesthetics. For example, L-pipecolic acid-2,6-xylidide is employed as an intermediate in the manufacturing of excellent topical anesthetics, for example, levobupivacaine and ropivacaine.
Numerous approaches have been proposed thus far with regard to methods of manufacturing pipecolamide derivatives, particularly in optically active forms thereof.
For example, (1) Japanese Examined Patent Publication (KOUKOKU) Heisei No. 5-59903 discloses a method of manufacturing pipecolamide derivatives by chloridizing pipecolic acid in advance to obtain pipecolic acid chloride, which is then reacted with an amine; (2) Publication of Japanese Translation of PCT International Application (KOUHYO) Heisei No. 10-507748 discloses a method of manufacturing pipecolamide derivatives in a one-pot by reacting pipecolic acid hydrochloride with thionyl chloride to obtain pipecolic acid chloride, which is then reacted with an amine; and (3) Tetrahedron Lett., 27, 6399-6402 (1996) discloses a method of manufacturing pipecolamide derivatives in a four-step reaction employing a starting material in the form of L-lysine with a protected α-amino group.
However, in manufacturing method (1), acetyl chloride, which is difficult to handle, is employed as a reaction solvent. Further, pipecolic acid chloride must be isolated as an intermediate, rendering the manufacturing process complex and inefficient. Still further, careful attention is required in the handling of the acid chloride, which is highly reactive with water. Although manufacturing method (2) is an efficient one-pot manufacturing method not requiring isolation of pipecolic acid chloride, thionyl chloride is employed as an acid-chloridizing reagent, requiring care for human bodies and the environment with respect to equipments to handle harmful sulfurous acid gas generated during the reaction. Manufacturing method (3) is an industrially unsuitable manufacturing method involving numerous manufacturing steps and a diazonium intermediate presenting a risk of explosion. Therefore, these methods are insufficient.
Accordingly, it is an object of the present invention to provide a method of efficiently manufacturing pipecolamide derivatives, particularly in optically active forms thereof, without harmful gas by-products.
The present inventors conducted extensive research to solve the aforementioned problem. They discovered that it was possible to efficiently produce pipecolamide derivatives without protecting an imino group of pipecolic acid by reacting pipecolic acid with an amine in the presence of a certain type of condensing agent. They further discovered that optically active pipecolamide derivatives could be obtained without a decrease in optical purity during the reaction process when optically active pipecolic acid was employed as a starting material. The present invention was devised based on such knowledge.